Crnn loss of function rodent model

Abstract

This disclosure relates to a genetically modified rodent and use thereof as a rodent model. More specifically, this disclosure relates to rodent (e.g., mouse or rat) comprising a loss of function mutation in an endogenous Crnn (cornulin) gene, and to use of such a rodent animal as a rodent model of skin inflammation disorders (e.g., psoriasis).

What is claimed is: 
     
       1. A rodent whose genome comprises a loss of function mutation in an endogenous rodent Crnn gene at an endogenous rodent Crnn locus, wherein the mutation comprises a deletion of the sequence beginning from the nucleotide after the ATG start codon through the stop codon of the endogenous rodent Crnn gene, and wherein the rodent is a rat or a mouse. 
     
     
       2. The rodent of  claim 1 , wherein the Crnn locus comprises a reporter gene coding sequence that is inserted in-frame to the start (ATG) codon of the Crnn locus. 
     
     
       3. The rodent of  claim 2 , wherein the reporter gene is LacZ. 
     
     
       4. The rodent of  claim 2 , wherein the reporter gene is selected from the group consisting of luciferase, green fluorescent protein (GFP), enhanced GFP (eGFP), cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), DsRed, and MmGFP. 
     
     
       5. The rodent of  claim 1 , wherein the rodent is homozygous for the mutation. 
     
     
       6. The rodent of  claim 1 , wherein the rodent is heterozygous for the mutation. 
     
     
       7. An isolated cell or tissue of the rodent of  claim 1 , wherein the genome of the isolated cell or tissue comprises the loss of function mutation in the endogenous rodent Crnn gene at the endogenous rodent Crnn locus. 
     
     
       8. A rodent embryonic stem (ES) cell whose genome comprises a loss of function mutation in an endogenous rodent Crnn gene at an endogenous rodent Crnn locus wherein the mutation comprises a deletion of the sequence beginning from the nucleotide after the ATG start codon through the stop codon of the endogenous rodent Crnn gene, and wherein the rodent ES cell is a rat cell or a mouse cell. 
     
     
       9. A rodent embryo comprising the ES cell of  claim 8 . 
     
     
       10. A method of making a rodent, the method comprising
 modifying a rodent genome such that the modified rodent genome comprises a loss of function mutation in an endogenous rodent Crnn gene at an endogenous rodent Crnn locus, wherein the mutation comprises a deletion of the sequence beginning from the nucleotide after the ATG start codon through the stop codon of the endogenous rodent Crnn gene, and 
 obtaining a rodent comprising the modified genome, wherein the rodent is a rat or a mouse. 
 
     
     
       11. A method of making a rodent, the method comprising
 introducing a nucleic acid sequence into a rodent ES cell, wherein the rodent ES cell is a rat ES cell or a mouse ES cell, wherein the nucleic acid sequence is integrated into an endogenous rodent Crnn locus in the rodent ES cell and results in a loss of function mutation in the endogenous rodent Crnn gene at the Crnn locus, and wherein the mutation comprises a deletion of the sequence beginning from the nucleotide after the ATG start codon through the stop codon of the endogenous rodent Crnn gene, thereby obtaining a rodent ES cell comprising a modified genome;
 and 
 making a rodent comprising the modified genome by using the rodent ES cell comprising the modified genome, wherein the rodent is a rat or a mouse. 
 
 
     
     
       12. A method of screening for a compound useful for treating skin inflammation, the method comprising
 providing a rodent according to  claim 1 , 
 applying imiquimod (IMQ) topically on the skin of the rodent to induce skin inflammation; 
 administering a candidate compound to the rodent; 
 measuring skin inflammation in the rodent to determine whether the candidate compound reduces skin inflammation in the rodent. 
 
     
     
       13. The method of  claim 12 , further comprising
 providing a wild type rodent without the mutation, 
 applying IMQ topically on the skin of the wild type rodent to induce skin inflammation; 
 administering the candidate compound to the wild type rodent; 
 measuring skin inflammation in the wild type rodent; and 
 determining whether the candidate compound reduces skin inflammation in the rodent with the mutation to the level of the wild type rodent.